The Initiation, but Not the Persistence, of Experimental Spondyloarthritis Is Dependent on Interleukin-23 Signaling

IL-17A is a central driver of spondyloarthritis (SpA), its production was originally proposed to be IL-23 dependent. Emerging preclinical and clinical evidence suggests, however, that IL-17A and IL-23 have a partially overlapping but distinct biology. We aimed to assess the extent to which IL-17A-dr...

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Published in:	Frontiers in immunology Vol. 9; p. 1550
Main Authors:	van Tok, Melissa N, Na, Songqing, Lao, Christopher R, Alvi, Marina, Pots, Desirée, van de Sande, Marleen G H, Taurog, Joel D, Sedgwick, Jonathon D, Baeten, Dominique L, van Duivenvoorde, Leonie M
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 09-07-2018
Subjects:	animal models HLA-B27 tg rats IL-17A IL-23 signaling IL-23R Immunology spondyloarthritis HLA-B27 tg rats spondyloarthritis IL-23R animal models IL-17A IL-23 signaling experimental spondyloarthritis
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Summary:	IL-17A is a central driver of spondyloarthritis (SpA), its production was originally proposed to be IL-23 dependent. Emerging preclinical and clinical evidence suggests, however, that IL-17A and IL-23 have a partially overlapping but distinct biology. We aimed to assess the extent to which IL-17A-driven pathology is IL-23 dependent in experimental SpA. Experimental SpA was induced in HLA-B27/Huβ2m transgenic rats, followed by prophylactic or therapeutic treatment with an anti-IL23R antibody or vehicle control. Spondylitis and arthritis were scored clinically and hind limb swelling was measured. Draining lymph node cytokine expression levels were analyzed directly , and IL-17A protein was measured upon restimulation with PMA/ionomycin. Prophylactic treatment with anti-IL23R completely protected against the development of both spondylitis and arthritis, while vehicle-treated controls did develop spondylitis and arthritis. In a therapeutic study, anti-IL23R treatment failed to reduce the incidence or decrease the severity of experimental SpA. Mechanistically, expression of downstream effector cytokines, including IL-17A and IL-22, was significantly suppressed in anti-IL23R versus vehicle-treated rats in the prophylactic experiments. Accordingly, the production of IL-17A upon restimulation was reduced. In contrast, there was no difference in IL-17A and IL-22 expression after therapeutic anti-IL23R treatment. Targeting the IL-23 axis during the initiation phase of experimental SpA-but not in established disease-inhibits IL-17A expression and suppresses disease, suggesting the existence of IL-23-independent IL-17A production. Whether IL-17A can be produced independent of IL-23 in human SpA remains to be established.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology Reviewed by: Sergei Koralov, NYU School of Medicine, United States; Hsien-bin Huang, National Chung Cheng University, Taiwan Edited by: Massimo Gadina, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), United States
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2018.01550